The damaging effects of radiation, particularly sunlight, on skin are well documented. Much damage is due to routine day-to-day activities in the sunlight.
The major short term hazard of prolonged exposure to sunlight is erythema (i.e., sunburn). The 290 to 320 nanometer wavelength ultraviolet radiation range, designated as the "UVB" wavelength range, tends to be the primary cause of erythema. The 320 to 400 nanometer wavelength ultraviolet radiation range, designated as the "UVA" wavelength range, also produces erythema.
In addition to the short term hazard of erythema, there are also long term hazards associated with UV radiation exposure. One of these long term hazards is malignant changes in the skin surface. Numerous epidemiologic studies demonstrate a strong relationship between sunlight exposure and human skin cancer. Another long term hazard of ultraviolet radiation is premature aging of the skin. This condition is characterized by wrinkling and yellowing of the skin, along with other physical changes such as cracking, telangiectasis (spider vessels), solar keratoses (growths), ecchymoses (subcutaneous hemorrhagic lesions), and loss of elasticity (sagging). The adverse effects associated with exposure to UVA and UVB wavelength radiation are more fully discussed in DeSimone, "Sunscreen and Suntan Products", Handbook of Nonprescription Drugs, 7th Ed, Chapter 26, American Pharmaceutical Association, Washington, D.C., 1982, pp. 499-511; Grove and Forbes, "A Method for Evaluating the Photoprotection Action of Sunscreen Agents Against UV-A Radiation", International Journal of Cosmetic Science, vol. 4 (1982), pp. 15-24; and U.S. Pat. No. 4,387,089 issued to DePolo on Jun. 7, 1983. Although the immediate effects of ultraviolet radiation may be cosmetically and socially gratifying, the long-term hazards are cumulative and potentially serious.
Sunblock agents are commercially available to protect the skin from UV radiation. These agents scatter or reflect ultraviolet radiation. Examples include titanium dioxide and zinc oxide. However, these agents are very susceptible to rub-off or wear-off, resulting in little or no protection.
The most common agents for sun protection are sunscreens. These agents exert their effects through absorption of ultraviolet radiation so that it cannot penetrate the skin. Sunscreens must remain on the surface of the skin during exposure to be effective. However, sunscreens are easily rubbed off or washed off by sweating or swimming and can also be lost by penetration into the skin.
Tocopherol (Vitamin E) and its esters have been disclosed for use as photoprotectors in topical compositions, without interfering with the tanning response; see, e.g., U.S. Pat. Nos. 4,144,325 issued to Voyt on Mar. 13, 1974; 4,248,861 issued to Schutt on Feb. 3, 1981; 4,000,276 issued to Hasunuma et al., on Dec. 28, 1976; 4,847,071 issued to Bissett, Bush & Chatterjee on Jul. 11, 1989; and European Patent Application No. 166,221 of Tuominen published Jan. 2, 1986.
Hart, J. R., "Chelating Agents in Cosmetic and Toiletry Products", Cosmetics and Toiletries, Vol. 93, No. 12 (1978), pp. 28-30, discloses the utilization of low levels of chelating agents such as ethylenediaminetetraacetic acid (EDTA) in cosmetic formulations as preservatives. Particularly disclosed is the use of EDTA in sunscreen lotions and creams to prevent dark color formation from the reaction of p-aminobenzoic acid derivatives with iron; see also, Hart, J. R., "EDTA-Type Chelating Agents in Personal Care Products", Cosmetics and Toiletries, Vol. 98, No. 4 (1983), pp. 54-58. Japanese Patent Application 61-215,314 discloses a topical composition for protecting skin from UV-rays containing EDTA or a phosphoric acid or salt, 4-(1,1-dimethylethyl)-4'-methoxydibenzoylmethane and inorganic powders. The acids and their salts are added as preservatives; see also, Japanese Patent Application 61-215,313, published Sep. 25, 1986; and U.S. Pat. No. 4,579,844 issued to Rovee on Apr. 1, 1986. Wooley, D. E., R. W. Glanville, D. R. Roberts & J. M. Evanson, "Purification, Characterization and Inhibition of Human Skin Collagenase", Biochem. J., Vol. 169 (1978), pp. 265-276, discloses the inhibition of skin collagenase utilizing EDTA, 1,10-phenanthroline, cysteine, dithiothreitol, or sodium aurothiemaleate.
It is well-known that various types of radiation, particularly ultraviolet light radiation, induce inflammation of the skin and harmful photochemical reactions therein. During exposure, and as repair of the radiation damage takes place, super-oxide (O.sub.2.sup.-) radicals are formed in the skin. UV irradiation also causes some microvascular damage in the skin; see Kligman, L. H. & A. M. Kligman, "The Nature of Photoaging: Its Prevention and Repair", Photodermatology, Vol. 3 (1986), pp. 215-227. This leads to local hemorrhage and "leakage" of blood cells into the dermis. Iron from the hemoglobin accumulates in the extra-cellular matrix of the tissue as Fe.sup.+2 and Fe.sup.+3. It is known that iron catalytically participates in the conversion of superoxide radicals to hydroxyl radicals, a species which is known to be very damaging to tissue; see Davies, K. J. A., M. E. Delsignore & S. W. Lin, "Protein Damage and Degradation by Oxygen Radicals. II. Modification of Amino Acids", The Journal of Bioloqical Chemistry, Vol. 262, No. 20 (1987), pp. 9902- 9907. Another process which is damaging to tissue is membrane lipid peroxidation, which is also accelerated by iron; see Halliwell and Gutteridge, Free Radicals in Biology and Medicine, Claredon Press, Oxford, England (1985), p. 147.
Black, H. S., "Potential Involvement of Free Radical Reactions in Ultraviolet Light-Mediated Cutaneous Damage", Photochemistry and Photobiology, Vol. 46, No. 2 (1987), pp. 213-221, speculates, based on circumstantial evidence, that free radicals may cause at least some UV-induced skin damage. The effect of systemically or intraperitoneally administered antioxidants on peroxide formation is discussed.
Nunez, M. T., E. S. Cole & J. Glass, "The Reticulocyte Plasma Membrane Pathway of Iron Uptake as Determined by the Mechanism of .alpha.,.alpha.'-Dipyridyl Inhibition", The Journal of Biological Chemistry, Vol. 258, No. 2 (1983), pp. 1146-1151, discusses the cellular mechanism by which iron is released by reticulocytes. It was found that iron (II) chelators (e.g., phenanthroline, dipyridyl), but not iron (III) chelators, were useful in the study of this mechanism.
deMello Filho, A. C. & R. Meneghini, "Protection of Mammalian Cells by o-Phenanthroline from Lethal and DNA-Damaging Effects Produced by Active Oxygen Species", Biochemica et Biophysica Acta, Vol. 847 (1985), pp. 82-89, describes cell culture work which suggests that the inhibition of the iron-initiated peroxidation reaction by phenanthroline may prevent cellular damage caused by inflammation.
Morgan, E. H. "Chelator-Mediated Iron Efflux from Reticulocytes". Biochemica et Biophysica Acta, Vol. 733, No. 1, (1983), pp. 39-50, discusses the mechanism by which certain iron chelators inhibit cellular iron uptake after release from transferrin while it is still in the membrane fraction of the cells.
Bissett, D. L., R. Chatterjee & D. P. Hannon, "Chronic Ultraviolet Radiation-Induced Increase in Skin Iron and the Photoprotective Effect of Topically Appl led Iron Chelators", Photochemistry and Photobiology, Vol. 54, No. 2 (1991), pp. 215-223, discloses that iron may have a role in skin photo-damage by participating in formation of reactive oxygen species, such as hydroxyl radical, and that certain iron chelators delay the onset of skin photodamage.
European Patent Application No. 0 313 305 of Bissett, Bush & Chatterjee published April 26, 1989, discloses photoprotection compositions comprising various chelating agents.
References which disclose certain substituted phenyl-1,3-diketones and various uses for such compounds include the following: U.S. Pat. Nos. 3,937,737 and 4,082,807 issued to Eiglmeier on Feb. 10, 1976 and Apr. 4, 1978, respectively; U.S. Pat. No. 3,994,869 issued to Gontarz & Nelson on Nov. 30, 1976; U.S. Pat. No. 4,015,980 issued to MacKay & Sudderth on Apr. 5, 1977; U.S. Pat. No. 4,123,400 issued to Gay on Oct. 31, 1978; U.S. Pat. No. 4,152,396 issued to MacKay & McDonald on May 1, 1979; U.S. Pat. No. 4,175,012 issued to McKay & Rogier on Nov. 20, 1979; and Belgian Patent No. 856,814 of Hoechst AG, published Oct. 31, 1977.
Substituted phenyl-1,3-diketone compounds disclosed to have ultraviolet light absorbing properties are disclosed in the following references: U.S. Pat. Nos. 4,387,089 issued to DePolo on Jun. 7, 1983; U.S. Pat. No. 4,489,057 issued to Welters, Gehlhaus & Moeschl on Dec. 18, 1984; U.S. Pat. No. 4,710,373 issued to Nakamura, Hattori, Tamura, Tajima, Takaishi, Imokawa & Hotta on Dec. 1, 1987; U.S. Pat. No. 4,988,501 issued to Gosciniak on Jan. 29, 1991; and Japanese Patent Publication No. 02,227,484-A of Hasegawa KK, published Sep. 10, 1990; and European Patent Application No. 0,431,755 of Unilever PLC, published Jun. 12, 1991.
It is an object of the subject invention to provide topical pharmaceutical compositions which provide protection against damage to the skin from sun exposure and other radiation sources.
It is also an object of the subject invention to provide methods for preventing damage to the skin due to exposure of skin to the sun and other radiation sources.
It is a further object of the subject invention to provide methods for preventing damage to the skin due to metal-catalyzed free radical generation in the cells of the skin.